Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Jialiang S Wang; Tushar Kamath; Courtney M Mazur; Fatemeh Mirzamohammadi; Daniel Rotter; Hironori Hojo; Christian D Castro; Nicha Tokavanich; Rushi Patel; Nicolas Govea; Tetsuya Enishi; Yunshu Wu; Janaina da Silva Martins; Michael Bruce; Daniel J Brooks; Mary L Bouxsein; Danielle Tokarz; Charles P Lin; Abdul Abdul; Evan Z Macosko; Melissa Fiscaletti; Craig F Munns; Pearl Ryder; Maria Kost-Alimova; Patrick Byrne; Beth Cimini; Makoto Fujiwara; Henry M Kronenberg; Marc N Wein

doi:10.1038/s41467-021-26571-7

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin

Nat Commun. 2021 Nov 1;12(1):6271. doi: 10.1038/s41467-021-26571-7.

Authors

Jialiang S Wang¹, Tushar Kamath^{2

3}, Courtney M Mazur¹, Fatemeh Mirzamohammadi^{1

4}, Daniel Rotter^{1

5}, Hironori Hojo⁶, Christian D Castro¹, Nicha Tokavanich¹, Rushi Patel¹, Nicolas Govea^{1

7}, Tetsuya Enishi^{1

8}, Yunshu Wu^{1

9}, Janaina da Silva Martins¹, Michael Bruce¹, Daniel J Brooks^{1

10}, Mary L Bouxsein^{1

10}, Danielle Tokarz^{11

12}, Charles P Lin¹¹, Abdul Abdul^{2

3}, Evan Z Macosko^{2

3

13}, Melissa Fiscaletti¹⁴, Craig F Munns^{15

16}, Pearl Ryder^{2

17}, Maria Kost-Alimova^{2

18}, Patrick Byrne^{2

18}, Beth Cimini^{2

17}, Makoto Fujiwara¹⁹, Henry M Kronenberg¹, Marc N Wein^{20

21

22}

Affiliations

¹ Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁴ Department of Plastic and Reconstructive Surgery, Wright State University, Dayton, OH, USA.
⁵ University of Applied Sciences Technikum Wien, Vienna, Austria.
⁶ Center for Disease Biology and Integrative Medicine, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
⁷ Department of Anesthesiology, Weill Cornell Medical School, New York, NY, USA.
⁸ Department of Orthopedic Surgery, Tokushima Municipal Hospital, Tokushima, Japan.
⁹ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
¹⁰ Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MaA, USA.
¹¹ Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Chemistry, Saint Mary's University, Halifax, Canada.
¹³ Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁴ Pediatric Department, Sainte-Justine University Hospital Centre, Montreal, Canada.
¹⁵ Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia.
¹⁶ Discipline of Paediatrics & Child Health, University of Sydney, Sydney, 2006, Australia.
¹⁷ Broad Institute of Harvard and MIT, Imaging Platform, Cambridge, MA, USA.
¹⁸ Broad Institute of Harvard and MIT, Center for the Development of Therapeutics, Cambridge, MA, USA.
¹⁹ Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
²⁰ Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. mnwein@mgh.harvard.edu.
²¹ Broad Institute of Harvard and MIT, Cambridge, MA, USA. mnwein@mgh.harvard.edu.
²² Harvard Stem Cell Institute, Cambridge, MA, USA. mnwein@mgh.harvard.edu.

Abstract

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7^R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Animals
Bone Diseases / genetics
Bone Diseases / metabolism*
Bone Diseases / physiopathology
Dendrites / metabolism*
Female
Gene Expression Regulation
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Muscle Proteins / genetics
Muscle Proteins / metabolism*
Mutation
Osteocytes / metabolism*
Sp7 Transcription Factor / genetics
Sp7 Transcription Factor / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Muscle Proteins
OSTN protein, human
Ostn protein, mouse
Sp7 Transcription Factor
SP7 protein, human
Sp7 protein, mouse
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding